Topical antifungal composition

ABSTRACT

A topical, foamable composition is provided that includes at least one antifungal agent that is able to penetrate the upper layers of skin and is retained in or on an area to be treated for a prolonged period of time, and that has a residual non-volatile component content less than 25%. In addition, a method of treating fungal diseases including jock itch, tinea, dandruff and sebborheic dermatitis is provided, and includes applying to the affected area of patient requiring such treatment an antifungal composition.

This is a Continuation Application of U.S. patent application Ser. No.12/293,000, filed on Dec. 2, 2008, which is a Continuation Applicationof U.S. patent application Ser. No. 09/529,033, filed on Apr. 5, 2000, aNational Phase Application filed under 35 USC 371 of InternationalApplication No. PCT/AU98/00867, filed on Oct. 19, 1998, an applicationclaiming foreign priority benefits under 35 USC 119 of AustralianApplication No. PO 9838, filed on Oct. 17, 1997, and claiming foreignpriority benefits under 35 USC 119 of Australian Application No. PP1217, filed on Jan. 6, 1998, the content of each of which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to a foamable antifungal composition forthe treatment of various skin conditions.

Antifungal agents are well known, and include macrolide antibiotics suchas griseofulvin, and imidazoles such as clotrimazole and ketoconazole.

Ketoconazole was originally described by Heeres et al in U.S. Pat. No.4,335,125, in which its principal utility was an antifungal compounduseful in the treatment of a variety of conditions including sebborheicdermatitis, dandruff, “jock itch” and tinea.

Antifungal compositions are traditionally applied as lotions or creams.There are however disadvantages to these forms. In particular, theformulations are frequently very viscous requiring substantial rubbingto achieve penetration into the effected area, an act in itself whichcauses discomfort and sometimes irritation. If the viscous formulationsare not vigorously applied, the active antifungal agent does notnecessarily reach the site requiring treatment being the epidermis ofthe skin. Non-viscous creams and lotions are wont to flow off theeffected site before penetration is achieved. One final disadvantage isthat cream and lotion bases in themselves can add to site irritationdepending on their content.

Ketoconazole was disclosed in U.S. Pat. No. 4,569,935 to be useful inthe topical treatment of psoriasis and seborrheic dermatitis. Pursuantto this utility, ketoconazole has been marketed in a 2% shampooformulation for the treatment of scaling due to dandruff, sold under thebrand name “Nizoral®”. This shampoo is applied by the user and thenremoved shortly, for example 3-5 minutes, after its application byrinsing with water. The active agent is thus only in contact with thearea to be treated for a very limited time.

Another patent describing ketoconazole based shampoos is U.S. Pat. No.5,456,851 in the name of JOHNSON & JOHNSON CONSUMER PRODUCTS, INC whichaims to provide good cosmetic properties to the shampoo includinglather, and to retard degradation of the ketoconazole. This compositionis a foaming formulation.

The disadvantage of such shampoo formulations is that during normalusage, the formulation does not remain on the scalp for a period of timesufficient to allow the antifungal agent to achieve its maximaltherapeutic effect since they are designed to be applied, for example inthe shower or bath, and shortly after rinsed off with water. Typically,the application instructions for such shampoos suggest that theformulation be removed after 3-5 minutes.

In order to achieve maximal therapeutic effect, one alternative such asis described in AU 80257/87, is to provide a high quantity of residualsolids which remain after application to treat the offending skincondition. There is disclosed in AU 80257/87 a foam composition for thedelivery of minoxidil. The formulations disclosed in this document allcontain a high percentage of non-volatile residues, including propyleneglycol. While it is not disclosed why these formulations contain such alarge amount of propylene glycol, it is postulated that the propyleneglycol is probably required either to enhance the penetration and/or toimprove the solubility of the minoxidil. The disadvantage of acomposition with a high residual content is that the non-volatileresidues are retained at the site of application and therefore feelunpleasant and unattractive to the user.

Alternatives to ketoconazole and minoxidil are described inAU-A-35717/93 in the name of SMITH KLINE BEECHAM PLC which disclosescompositions including a novel androstene steroid for use in thetreatment of acne and sebborrhea, and AU-A-48851/96 in the name ofMEDEVA PLC which describes the use of betamethasone in a quick breakingfoam including a buffering agent for use in the treatment of skindiseases and particularly scalp psoriasis.

It is an aim of this invention to provide an antifungal compositionwhich is effective in its treatment of fungal skin conditions but whichis also pleasant to use.

SUMMARY OF THE INVENTION

To this end, in a first aspect of the invention, there is provided atopical, foamable composition including at least one antifungal agent,said composition characterised in that said at least one antifungalagent is able to penetrate the upper layers of the skin and is retainedin or on an area to be treated for a prolonged period of time, and inthat it has a residual non-volatile component content of less that 25%.

It has been surprisingly found that the antifungal composition of thepresent invention has a commercially acceptable cosmetic appeal andduring normal usage allows greater penetration and retention of theantifungal agent in the upper layers of the skin, particularly in theepidermis, thus providing a reservoir of active agent available toachieve a sustained antifungal effect when compared against knownformulations. This latter feature leads to enhanced pharmaceuticalappeal as well as cosmetic appeal. Moreover, the residual solids contentof the formulation is so low as to not provide discomfort and irritationto the user

The term “prolonged period of time” is meant to encompass periods oftime sufficiently long so as to enable the active agent present to besubstantially fully absorbed by the organism being treated, orsubstantially fully metabolised by the patient being treated.

In a preferred embodiment, the one or more antifungal agents is selectedfrom the group consisting of diols, allylamines (including naftifine andterbinafine), polyene macrolide antibiotics (including amphotericin andnystatin), triazole derivatives (such as fluconazole), fatty acids (suchas caprylic and propionic acid), amorolfine, ciclopirox, olamine,benzoic acid, flucytosine, haloprogin, tolnaftate, undecenoic acid andits salts, griseofulvin and imidazole compounds. More preferably, theantifungal is an imidazole compound. Most preferably, the antifungalagent is ketoconazole or chlorphenesin(3-(4-Chlorphenoxy)propane-1,2-diol).

Preferably the compositions according to the invention have a residualnon-volatile component content of less that 10%, and more preferably ofless than 6%.

In a preferred embodiment the topical, foamable composition is providedas a mousse.

in a further preferred embodiment the mousse is a temperature sensitivemousse, which breaks down rapidly when exposed to the skin temperature.

In a still further embodiment, the composition is an ethanolic mousseincluding a lower alcohol content of greater than 10%, more preferablygreater than 50% and a hydrocarbon gas content propellent of less than60%, more preferably less than 10%.

In an alternative embodiment the composition is an aqueous mousseincluding no lower alcohol content and a hydrocarbon gas contentpropellent of less than 60%, more preferably less than 10%.

(Unless specified otherwise in the specification, all % are based on thetotal weight of the composition.)

In the temperature sensitive mousse, the long chain alcohol may bechosen from, for example, cetyl, stearyl, lauryl, myristyl and palmitylalcohols and mixtures of two or more thereof.

The lower alcohol may preferably be chosen from methyl, ethyl, isopropyland butyl alcohols, and mixtures of two or more thereof. Ethanol hasbeen found to be particularly preferred.

Surfactants utilised in the temperature sensitive mousse may preferablybe chosen from ethoxylated sorbitan stearate, palmitate, oleate, nonylphenol ethoxylates and fatty alcohol ethoxylates, and mixtures of two ormore thereof. Thus, for example, Polysorbate 60 (a mixture of partialstearic esters of sorbitol and its anhydrides copolymerised withapproximately 20 moles of ethylene oxide for each mole of sorbitol andits anhydrides) has been found to be particularly preferred. Thesurfactant enhances the long chain alcohol solubility in the system andenhances mousse formation.

In a further aspect of the invention, there is provided a foamablecomposition including

up to 5% of long chain alcohols

up to 5% of quaternary compound

up to 10% of propylene glycol

up to 5% of antifungal agent

up to 90% of lower alcohol solvent

up to 5% of surfactant

5-95% of water, and

up to 20% of a hydrocarbon gas propellant

Preferably, the long chain alcohol is cetyl or stearyl alcohol ormixtures thereof.

Preferably, the quaternary compound is quaternium oxy ethyl alkylammonium phosphate commercially available under the trade name,Dehyquart SP.

Preferably, the lower alcohol solvent is ethanol or propanol or mixturesthereof.

Suitable gas propellants include non-toxic gas propellants suited tofoamable cosmetic and pharmaceutical compositions and known to thoseskilled in the art.

Thus, one may select the propellant from propane, butane, dichlorodifluoro methane, dichloro tetrafluoro ethane, octafluoro cyclobutane,and mixtures of two or more thereof. It is necessary to select apropellant most compatible with the entire system. The maximum level ofpropellant will be determined as the amount miscible with the utilizedwater/lower alcohol ratio. In addition to acting as a propellant, thepropellant will also act as a solvent for the long chain alcohol andactive substances in the aqueous/alcoholic system.

In a second aspect of the invention there is provided a composition forthe treatment of fungal skin conditions including dandruff, seborrheicdermatitis, tinea, jock itch and the like, said compositioncharacterised in that it is a foamable mousse applicable to the skin ofthe user in the substantial absence of water and without substantiallyimmediate removal by washing.

In a preferred embodiment of this aspect of the invention, saidcomposition has a non-volatile component content of less than 25%,preferably less than 10% and more preferably less than 6%.

In a more preferred embodiment of this aspect of the invention, themousse is a temperature sensitive mousse, which breaks down rapidly whenexposed to the skin temperature.

In a still further preferred embodiment, the composition is a mousseincluding a lower alcohol content of greater than 10%, more preferablygreater than 50% and a hydrocarbon gas content propellent of less than60%, more preferably less than 10%.

In a further aspect of the invention there is provided a topical,foamable composition including an antifungal agent characterised in thatupon application to the skin of a user a penetration of at feast 10μg/cm² is achieved in the epidermis within one hour of application andsustained over a period of at least 23 hours.

When the preferred active agent is ketoconazole, the invention providesa topical, foamable composition characterised in that upon applicationto the skin of a user a penetration of at least 30 μg/cm² is achieved inthe epidermis within one hour of application and sustained over a periodof at least 23 hours.

When the preferred active agent is chlorphenesin, the invention providesa topical, foamable composition characterised in that upon applicationto the skin of a user a penetration of at least 10 μg/cm² is achieved inthe epidermis within one hour of application and sustained over a periodof at least 23 hours.

In a still further aspect of the invention, there is provided a methodof treating fungal infections, particularly tinea, jock itch, dandruffand sebborheic dermatitis by applying to the affected area of a patientrequiring such treatment the antifungal composition of the presentinvention.

In a preferred embodiment of this aspect of the invention, thecomposition is allowed to remain on the affected area for an extendedperiod of time.

In this context “extended period of time” means a length of time greaterthan the length of time that prior art topical compositions such asshampoos are prescribed to remain in contact with the affected area.Usually, shampoos are designed to be washed off within 5 minutes.

More preferably, when the composition is used to treat dandruff orsebborheic dermatitis, it is applied at one wash or between washes andis allowed to remain on the site of application such as the scalp orhair until the site of application is subsequently washed again.

The invention also encompasses the use of an antifungal agent in thepreparation of a topical foamable composition for the treatment offungal diseases including dandruff, tinea, jock itch and sebborheicdermatitis, the topical foamable composition being characterised in thatit is able to penetrate the epidermis of the skin and is retained in oron an area to be treated for a prolonged period of time, and in that ithas a non-volatile component content of less that 25%.

DETAILED DESCRIPTION OF THE INVENTION

Two formulations of the present invention were prepared.

1) 0.5% ketoconazole mousse composition

Cetyl alcohol 1.10 Stearyl alcohol 0.50 Quaternium 52 (50%) 1.00Propylene Glycol 2.00 Ketoconazole USP 0.50 Ethanol 95PGF3 60.55Deionised Water 30.05 P75 Hydrocarbon Propellant 4.30

2) 1% ketoconazole mousse composition

Cetyl alcohol 1.10 Stearyl alcohol 0.50 Quaternium 52 (50%) 1.00Propylene Glycol 2.00 Ketoconazole USP 1.00 Ethanol 95PGF3 60.20Deionised Water 29.90 P75 Hydrocarbon Propellant 4.30

The compositions were prepared by dissolving the active in the ethanol.the cetyl and stearyl alcohol are then added to the heated solution andmixed until dissolved. The quaternium 52, propylene glycol and water arethen added and stirred until homogenous, while maintaining the elevatedtemperature. The solution is then dispensed into aerosol cans where theaerosol valve is then fitted and the can charged with propellant.

Example 1

A study was undertaken to compare the epidermal penetration of the twomousse compositions above, against the commercially available Nizoral®shampoo containing 2% ketoconazole. In particular the respectiveformulations were applied and removed as for a conventional shampoo soas to compare the penetration of the respective formulations into theepidermis.

Equipment and Materials

in vitro Franz diffusion cells (surface area 1.33 cm², receptor volume3.5 ml) incorporating human epidermis

HPLC equipment: Shimadzu automated HPLC system with uv detector, bovineserum albumin dissolved in phosphate buffered saline (pH 7.4) asreceptor phase to mimic physiological conditions.

Experimental Protocol

finite dosing (50 mg for shampoo and 100 mg for mousses)

receptor phase: 4% BSA in phosphate buffered saline at pH 7.4 samplingtime: 6, 10, 24 hours (amount in receptor phase (μg/cell) and epidermis(μg/cell)) non-occlusion study

each time period and formulation conducted in triplicate.

Application Procedure

-   Shampoo: 50 mg shampoo (equivalent to 1 mg ketoconazole)    -   dose applied to pre-wetted skin with stirring and rinsed off        with deionised water after 4 minutes.-   Mousse: 100 mg mousse (equivalent to 1 mg ketoconazole for 1% mousse    and 500 μg ketoconazole for 0.5% mousse    -   dose applied (not rinsed off).        Epidermal Retention Protocol

Epidermis removed from cell following time interval, rinsed withdistilled water and dried to remove ketoconazole remaining on surface.Ketoconazole extracted from epidermal sample by soaking in methanol for1 hour. This procedure is repeated with a second volume of methanol for30 mins. The methanol samples are combined for HPLC analysis (thisprocedure has been validated with a 99% recovery rate).

HPLC Assay

Column: Nova Pak C₁₈ steel column, 3.9×150 mm

Mobile phase: 70% MeOH in 0.02 M phosphate buffer, pH 6.8

Wavelength: 254 nm

Flow rate: 1.3 ml/min

Injection volume: 10

Retention time: about 7 min

Results

Table 1 shows the cumulated ketoconazole in both the receptor phase andthe epidermis at defined time points following application of the mousseaccording to the invention and the shampoo of the prior art.

TABLE 1 Ketoconazole μg/cell 6 hours 10 hours 24 hours Sample receptorepidermis receptor epidermis receptor epidermis 0.5% mousse 4.96 33.159.04 69.46 14.69 42.10 0.5% mousse 2.83 35.71 18.06 48.04 24.77 39.190.5% mousse 14.37 34.3 21.3 55.29 9.82 48.27 Mean ± SD 7.4 ± 6.1 34.4 ±1.3  16.1 ± 6.4  57.6 ± 10.9 16.4 ± 7.6  43.2 ± 4.6   1% mousse 12.8646.4 31.50 67.51 21.90 51.43   1% mousse 10.03 61.8 11.05 55.65 35.8546.64   1% mousse 18.61 38.6 19.38 56.83 10.72 43.28 Mean ± SD 13.8 ±4.4   48.9 ± 11.8 20.6 ± 10.3  60 ± 6.5 22.8 ± 12.6 47.1 ± 4.1   2%shampoo N N N 0.89 N N   2% shampoo N N N 0.28 N 0.38   2% shampoo N N NN N 0.34 Mean ± SD — — — 0.39 ± 0.46 —  0.24 ± 0.21 N: not detectable(assuming to be zero for calculating mean and SD) —: not available

Table 2 shows the cumulated ketoconazole in both receptor (expressed asμg/ml receptor fluid) and epidermis (expressed as μg/cm² surface area)at defined time points following application of the mousse according tothe present invention and the shampoo of the prior art.

TABLE 2 Ketoconazole μg 6 hours 10 hours 24 hours Sample receptorepidermis receptor epidermis receptor epidermis 0.5% mousse 1.42 26.952.58 56.47 4.20 34.23 0.5% mousse 0.81 29.03 5.46 39.06 7.08 31.86 0.5%mousse 4.11 27.89 6.09 44.95 2.81 39.24 Mean ± SD 2.11 ± 1.76 27.96 ±1.04 4.61 ± 1.82 46.83 ± 8.86 4.70 ± 2.18 35.11 ± 3.77   1% mousse 3.6737.72 9.00 54.89 6.26 41.81   1% mousse 2.87 50.24 3.16 45.24 10.24 37.92   1% mousse 5.32 31.38 5.54 46.20 3.06 35.19 Mean ± SD 3.95 ± 1.2539.78 ± 9.60 5.90 ± 2.94 48.78 ± 5.31 8.52 ± 3.60 38.31 ± 3.33   2%shampoo N N N  0.72 N N   2% shampoo N N N  0.23 N  0.31   2% shampoo NN N N N  0.28 Mean ± SD — — —  0.32 ± 0.37 —  0.20 ± 0.17 N: notdetectable (assuming to be zero for calculating mean and SD) —: notavailable

FIG. 1 shows the time course of the ketoconazole penetrating acrosshuman epidermis to receptor fluid. The closed points of the graphrepresent 0.5% mousse, the open points represent 1.0% mousse. Data arethe mean±SD of triplicate (from Table 2).

FIG. 2 represents the time course of ketoconazole retained in theepidermis. The closed points of the graph represent 0.5% mousse, theopen points represent 1.0% mousse. Data are the mean±SD of triplicate(from Table 2).

FIG. 3 compares the levels of retention of ketoconazole on the skin, thelevels of retention of the ketoconazole in the skin and the amount ofketoconazole passed through the skin in the tests using a mousseaccording to the invention with the same measures using Nizoral®. Notethat ketoconazole levels found after application of the Nizoral® shampoowere low and thus are not visible in this figure

It can readily be observed from the results of example 1 that:

-   1. the ketoconazole in the mousse compositions of the present    invention penetrated the skin in appreciable quantity;-   2. the ketoconazole in the mousse composition of the present    invention was preferentially retained in the epidermis compared to    penetration into the receptor solution;-   3. application of the prior art shampoo, Nizoral®, resulted in    insignificant amounts of ketoconazole in the epidermis and    penetrating to the receptor phase at any of the time points    following application using a standardised shampooing procedure;-   4. comparison of the 1% and 0.5% mousse formulations of the present    invention shows that there is little difference in epidermal and    receptor phase concentrations.

Example 2

A second study was undertaken to compare the skin penetration andretention of ketoconazole from the 1% ketoconazole mousse composition ofthe current invention with Nizoral® Shampoo (1% w/w). The 1% moussecomposition had a total residue content of 5.1% solids including active.

Equipment and Materials

In vitro Franz diffusion cells (surface area 1.33 cm², receptor volume3.5 mL) incorporating full thickness human skin,

HPLC equipment: Shimadzu automated HPLC system with uv detector.

Experimental Protocol

Finite dosing (50 mg of each formulation placed onto skin surface),Receptor phase: 4% bovine serum albumin (BSA) in phosphate bufferedsaline (PBS) pH 7.4,

Sampling times for skin retention: 15 minutes, 1, 12, 24 hours,

Sampling times for skin penetration to receptor phase: 12, 24 hours,

Amount of ketoconazole in full thickness skin and receptor phasemeasured by HPLC assay following suitable extraction procedure,

Non-occlusion study,

Triplicate measurements.

Application Procedure

Both mousse and shampoo were applied and left in contact with the skinfor the duration of the penetration study. Following this theformulation was washed off the skin with distilled water prior to sampleextraction procedure and HPLC assay for ketoconazole content.

HPLC Assay

Column: Nova Pac C₁₈ steel column, 3.9×150 mm (Waters)

Mobile phase: 70% MeOH in 0.02M PBS, pH 6.8

Wavelength: 254 nm

Flow rate: 1.0 mL/min

Injection volume: 10 μL

Retention time: approximately 8 mins

Full Thickness Ship Retention Protocol

Full thickness skin was removed from cell following time interval,rinsed with distilled water and dried to remove ketoconazole remainingon surface. Ketoconazole was extracted from full thickness skin sampleby soaking in methanol for 1 hour. This procedure was repeated with asecond volume of methanol for 30 mins. The methanol samples werecombined from HPLC analysis. [This procedure has been validated with a99% recovery rate].

Results

FIG. 4 shows the HPLC standard curve for ketoconazole.

Table 3 shows the amount of ketoconazole retained in the skin (μg/cm²)at 15, 60 minutes, 12 and 24 hours following application of the mousseaccording to the invention, or the shampoo of the prior art.

TABLE 3 Ketoconazole retained in skin (μg/cm²) at 15, 60 mins, 12, 24hours following application of mousse or shampoo. Ketoconazole in skin(μg/cm²) mean ± SEM Sample 15 mins 60 mins 12 hrs 24 hrs Shampoo 11.2 ±0.91 24.2 ± 1.58  39.7 ± 12.3  70.1 ± 18.8 Mousse 19.6 ± 2.5  44.1 ±8.27 128.37 ± 19.1 228.57 ± 14.8

Table 4 shows the amount of ketoconazole penetrated to the receptorphase (μg/mL) at 12, 24 hours following application of the mousseaccording to the invention, or the shampoo of the prior art.

TABLE 4 Ketoconazole penetrated to receptor phase (μg/mL) at 12, 24hours following application of mousse or shampoo. Ketoconazole inreceptor (μg/mL) mean ± SEM Sample 15 mins 60 mins 12 hrs 24 hrs Shampoo— — n 0.04 ± 0.04 Mousse — — 0.07 ± 0.05 0.30 ± 0.04 n: not detectable—: not assayed

FIG. 5 shows the amount of ketoconazole retained in the skin versus thetime after application of the formulation according to the invention.Data are the mean±SEM (n=3) from Table 4.

The mousse formulation according to the invention demonstratedsignificantly greater skin retention of ketoconazole than the shampooformulation of the prior art over the 24 hour period.

It can readily be observed from the results of example 2 that:

-   1. penetration of ketoconazole to the receptor phase over the 24    hours following application was minimal for both shampoo and mousse.-   2. skin retention of ketoconazole was significantly greater    following application of the mousse formulation compared to the    shampoo (p<0.05).

Example 3

A third study was undertaken to compare the skin penetration andretention of two formulations according to the invention in which theactive anti fungal agent was chlorphenesin (0.5% w/w). One formulationwas ethanolic and had a total residue content of 2.5% solids includingactive, the other formulation was aqueous and had a total residuecontent of 4.6% solids including active.

% w/w Aqueous formulation Chlorphenesin 0.50 Cetyl alcohol 0.70 Stearylalcohol 0.30 Icocetyl alcohol 2.50 Ceteth 20 0.50 Preservative 0.10Purified Water 90.40 P75 Hydrocarbon Propellant 5.00 Ethanolicformulation Chlorphenesin 0.50 Cetyl alcohol 1.10 Stearyl alcohol 0.50Polysorbate 0.40 Ethanol 95% 60.79 Purified Water 32.41 P75 HydrocarbonPropellant 4.30Equipment and Materials

In vitro Franz diffusion cells (surface area 1.33 cm², receptor volume3.5 mL) incorporating full thickness human skin,

HPLC equipment: Shimadzu automated HPLC system with uv detector.

Experimental Protocol

Finite dosing (50 mg of each formulation placed onto skin surface),

Receptor phase: 4% bovine serum albumin (BSA) in phosphate bufferedsaline (PBS) pH 7.4,

Sampling times for skin retention: 15 minutes, 1, 12, 24 hours,

Sampling times for skin penetration to receptor phase: 12, 24 hours,

Amount of chlorphenesin in full thickness skin and receptor phasemeasured by HPLC assay following extraction into acetonitrile (ACN) andmethanol (MeOH) (9:1),

Non-occlusion study,

Triplicate measurements.

Application

Mousses according to the invention were applied and left in contact withthe skin for the duration of the penetration study. Following this theformulation was washed off with distilled water prior to the extractionand HPLC for chlorphenesin content.

HPLC Assay

Column: Nova Pac C₁₈ steel column, 3.9×150 mm (Waters)

Mobile phase: 30% ACN

Wavelength: 280 nm

Flow rate: 1.0 mL/min

Injection volume: 20 μL

Retention time: approximately 3.6 mins

Skin Retention Protocol

Skin was removed form the cell following time interval and rinsed withdistilled water to remove chlorphenesin on the surface. Chlorphenesinwas extracted from homogenised skin by soaking in 1 mL ACN-MeOH mix for1 hour. This procedure was repeated for a further four 30 minuteperiods. The five samples were combined for HPLC analysis. [Theprocedure was validated with a 99% recovery rate].Results

FIG. 6 shows the HPLC standard curve for chlorphenesin. Data are themean±standard deviation (n=3).

Table 5 shows the amount of chlorphenesin retained in the skin (μg/cm²)at 15, 60 minutes, 12 and 24 hours following application of the mousseaccording to the invention.

TABLE 5 Chlorphenesin in skin (μg/cm²) mean ± SD Sample 15 mins 60 mins12 hrs 24 hrs aqueous 12.8 ± 4.8 13.2 ± 1.1 47.6 ± 13.2 35.8 ± 2.2 non-aqueous 16.7 ± 5.5   22 ± 9.7 93.8 ± 17.3 57.4 ± 20.4

Table 6 shows the amount of chlorphenesin penetrated to the receptorphase (μg/mL) at 12, 24 hours following application of the mousseaccording to the invention.

TABLE 6 Chlorphenesin in receptor (μg/mL) mean ± SD Sample 15 mins 60mins 12 hrs 24 hrs aqueous — — 2.9 ± 0.4 5.6 ± 1.1 non-aqueous — —   5 ±0.7 5.1 ± 1.5 — not assayed

FIG. 7 shows the amount of chlorphenesin retained in the skin versus thetime after application of the formulation according to the invention.Data are the mean±standard deviation (n=3) from Table 5. The open pointsare the aqueous formulation. The closed points represent the ethanolicformulation.

It is readily observed from the results of example 3 that active agentsother than ketoconazole formulated as both ethanolic and aqueouscompositions achieve the desired penetration and retention levels foreffective treatment of fungal skin conditions.

It will be appreciated that the scope of this invention goes beyond thespecific formulations exemplified to encompass topical foamableantifungal compositions having like components to those specificallymentioned but having characteristic penetration and retention levels inthe skin of the user, and low levels of residual solid content asdefined.

The claims defining the invention are as follows:
 1. A method fortreating fungal diseases, comprising: (a) providing a topical, foamablecomposition which in use produces a temperature sensitive,quick-breaking foam or mousse, the composition comprising: ketoconazole,wherein the ketoconazole is capable of penetrating the upper layers ofskin of a user, at least one surfactant, water, a lower alcohol, a longchain alcohol, and a hydrocarbon gas propellant content of less than 60%by weight; and wherein the composition has a residual non-volatilecomponent content of less than 25% by weight and is maintained at a pHranging from approximately 7 to approximately 8; and (b) applying thetopical, foamable composition to the user's skin, wherein theketoconazole is retained in or on skin for a period of time sufficientto achieve skin penetration.
 2. The method of claim 1, wherein the loweralcohol is ethanol with a content of greater than 50% by weight.
 3. Themethod of claim 1, wherein the topical foamable composition comprises:up to 5% by weight of long chain alcohol; up to 10% by weight ofpropylene glycol; up to 5% by weight of the ketoconazole; up to 90% byweight of lower alcohol; up to 5% by weight of surfactant; 5-95% byweight of water; and up to 20% by weight of the hydrocarbon gaspropellant.
 4. The method of claim 1, wherein the surfactant is selectedfrom the group consisting of ethoxylated sorbitan stearate, ethoxylatedsorbitan palmitate, ethoxylated sorbitan oleate, a nonyl phenolethoxylate and a fatty alcohol ethoxylate, and mixtures thereof.
 5. Themethod of claim 3, wherein upon application of the composition to theuser's skin, a penetration of at least 30 μg/cm² is achieved in theuser's epidermis within one hour of application and sustained over aperiod of at least 23 hours.
 6. The method of claim 1, wherein thecomposition remains on the user's skin for an extended period of time.7. A topical, foamable composition, comprising: (a) ketoconazole; (b) atleast one surfactant; (c) a lower alcohol content of greater than 50% byweight; (d) water; (e) a long chain alcohol; and (f) a propellant; andwherein the composition produces a temperature-sensitive, quick-breakingfoam or mousse when used and wherein the composition has a residualnon-volatile component content of less than 25% by weight and ismaintained at a pH ranging from approximately 7 to approximately
 8. 8.The composition of claim 7, wherein the composition is a mousse.
 9. Thecomposition of claim 8, wherein the propellant is a hydrocarbon gaspropellant in an amount of less than 60% by weight.
 10. The compositionof claim 7, wherein the lower alcohol is ethanol.
 11. The composition ofclaim 7, comprising: up to 5% by weight of long chain alcohol; up to 10%by weight of propylene glycol; up to 5% by weight of the ketoconazole;up to 90% by weight of lower alcohol; up to 5% by weight of surfactant;5-95% by weight of water; and up to 20% by weight of hydrocarbon gaspropellant.
 12. The composition of claim 7, wherein the surfactant isselected from the group consisting of ethoxylated sorbitan stearate,ethoxylated sorbitan palmitate, ethoxylated sorbitan oleate, a nonylphenol ethoxylate and a fatty alcohol ethoxylate, and mixtures thereof.13. A topical, foamable composition, comprising: (a) one or moreantifungal agents in an amount of up to 5% by weight, the one or moreantifungal agents comprising ketoconazole; (b) ethanol at greater than50% by weight and up to 90% by weight; (c) polyoxyethylene sorbitanmonostearate in an amount of up to 5% by weight; (d) up to 5% by weightcetyl alcohol or stearyl alcohol or mixtures thereof; (e) up to 10% byweight propylene glycol; (f) 5-95% by weight water; and (g) optionally apropellant; wherein the antifungal agent is retained in or on skin for aperiod of time sufficient to penetrate the epidermis of a user, andwherein the composition is maintained at a pH ranging from approximately7 to approximately
 8. 14. A method for treating fungal diseases,comprising: (a) providing a topical, foamable composition comprisingketoconazole, wherein the ketoconazole is capable of penetrating theupper layers of skin of a user, at least one surfactant, water, a loweralcohol content of greater than 10% by weight, a long chain alcohol, andhydrocarbon gas propellant in an amount of less than 60% by weight ofthe total composition, wherein the composition is a temperaturesensitive quick breaking foam or mousse and wherein the composition hasa residual non-volatile component content of less than 25% by weight andis maintained at a pH ranging from approximately 7 to approximately 8;and (b) applying the topical, foamable composition to the user's skin,wherein the ketoconazole is retained in or on skin for a period of timesufficient to achieve skin penetration.
 15. The method of claim 14,wherein the composition has a hydrocarbon gas propellant content of lessthan 10% by weight.
 16. The method of claim 14, wherein the providedtopical, foamable composition comprises: up to 5% by weight of longchain alcohol; up to 10% by weight of propylene glycol; up to 5% byweight of the ketoconazole; up to 90% by weight of lower alcohol; up to5% by weight of surfactant; 5-95% by weight of water; and up to 20% byweight of a hydrocarbon gas propellant.
 17. The method of claim 14,wherein the lower alcohol is ethanol and has a content of greater than50% by weight.
 18. The method of claim 14, wherein the long chainalcohol is selected from the group consisting of cetyl alcohol, stearylalcohol, and mixtures thereof.
 19. The method of claim 14, wherein thesurfactant is selected from the group consisting of ethoxylated sorbitanstearate, ethoxylated sorbitan palmitate, ethoxylated sorbitan oleate, anonyl phenol ethoxylate and a fatty alcohol ethoxylate, and mixturesthereof.
 20. The method of claim 16, wherein upon application of thecomposition to the user's skin, a penetration of at least 30 μg/cm² isachieved in the user's epidermis within one hour of application andsustained over a period of at least 23 hours.
 21. The method of claim14, wherein the composition remains on the user's skin for an extendedperiod of time.
 22. A topical, foamable composition comprising: (a)ketoconazole; (b) at least one surfactant; (c) a lower alcohol contentof greater than 10% by weight; (d) water; (e) a long chain alcohol; (f)hydrocarbon gas propellant in an amount of less than 60% by weight; andwherein the composition is a temperature-sensitive, quick-breaking foamor mousse, and wherein the composition has a residual non-volatilecomponent content of less than 25% by weight and is maintained at a pHranging from approximately 7 to approximately
 8. 23. The composition ofclaim 22, wherein the hydrocarbon gas propellant is present in an amountof less than 10% by weight.
 24. The composition of claim 22, comprising:up to 5% by weight of long chain alcohol; up to 10% by weight ofpropylene glycol; up to 5% by weight of the ketoconazole; up to 90% byweight of lower alcohol; up to 5% by weight of surfactant; 5-95% byweight of water; and up to 20% by weight of a hydrocarbon gaspropellant.
 25. The composition of claim 22, wherein the lower alcoholis ethanol and has a content of greater than 50% by weight.
 26. Thecomposition of claim 22, wherein the long chain alcohol is selected fromthe group consisting of cetyl alcohol, stearyl alcohol, and mixturesthereof.
 27. The composition of claim 22, wherein the surfactant isselected from the group consisting of ethoxylated sorbitan stearate,ethoxylated sorbitan palmitate, ethoxylated sorbitan oleate, a nonylphenol ethoxylate and a fatty alcohol ethoxylate and mixtures thereof.28. A method for treating fungal diseases, comprising: (a) providing atopical, foamable composition which in use produces atemperature-sensitive, quick-breaking foam or mousse, the compositioncomprising: ketoconazole, wherein the ketoconazole is capable ofpenetrating the upper layers of skin of a user, at least one surfactantselected from the group consisting of ethoxylated sorbitan stearate,ethoxylated sorbitan palmitate, ethoxylated sorbitan oleate, a nonylphenol ethoxylate and a fatty alcohol ethoxylate, water, a loweralcohol, a long chain alcohol, wherein the lower alcohol is ethanol witha content of greater than 50% by weight, and wherein the composition hasa residual non-volatile component content of less than 25% by weight andis maintained at a pH ranging from approximately 7 to approximately 8;and (b) applying the topical, foamable composition to the user's skin,wherein the ketoconazole is retained in or on skin for a period of timesufficient to achieve skin penetration.
 29. A topical, foamablecomposition, comprising: (a) ketoconazole; (b) at least one surfactantselected from the group consisting of an ethoxylated sorbitan stearate,ethoxylated sorbitan palmitate, ethoxylated sorbitan oleate, a nonylphenol ethoxylate and a fatty alcohol ethoxylate; (c) an ethanol contentof greater than 50% by weight wherein the ketoconazole is dissolved inthe ethanol; (d) water; (e) a long chain alcohol; and wherein thecomposition produces a temperature-sensitive, quick-breaking foam ormousse when used and wherein the composition has a residual non-volatilecomponent content of less than 25% by weight and is maintained at a pHranging from approximately 7 to approximately
 8. 30. A topical, foamablecomposition, comprising: (a) ketoconazole in an amount of up to 5% byweight, wherein the ketoconazole is capable of penetrating the upperlayers of skin of a user; (b) a lower alcohol content of greater than50% by weight and up to 90% by weight, wherein the lower alcohol isethanol; (c) at least one surfactant in an amount of up to 5% by weight,the at least one surfactant being selected from the group consisting ofethoxylated sorbitan stearate, ethoxylated sorbitan palmitate,ethoxylated sorbitan oleate, a nonyl phenol ethoxylate and a fattyalcohol ethoxylate; (d) up to 5% by weight of a long chain alcohol ormixtures thereof; (e) up to 10% by weight propylene glycol; and (f)5-95% by weight water; wherein the ketoconazole is retained in or onskin for a period of time sufficient to penetrate the epidermis of theuser, and wherein the composition is maintained at a pH ranging fromapproximately 7 to approximately
 8. 31. A method for treating fungaldiseases, comprising: (a) providing a topical, foamable compositioncomprising ketoconazole, wherein the ketoconazole is capable ofpenetrating the upper layers of skin of a user, at least one surfactantselected from the group consisting of ethoxylated sorbitan stearate,ethoxylated sorbitan palmitate, ethoxylated sorbitan oleate, a nonylphenol ethoxylate and a fatty alcohol ethoxylate, water, a lower alcoholcontent of greater than 10% by weight, a long chain alcohol, andhydrocarbon gas propellant in an amount of less than 60% by weight ofthe total composition, wherein the composition is a temperaturesensitive quick breaking foam or mousse, and wherein the composition hasa residual non-volatile component content of less than 25% by weight andis maintained at a pH ranging from approximately 7 to approximately 8;and (b) applying the topical, foamable composition to the user's skin,wherein the ketoconazole is retained in or on skin for a period of timesufficient to achieve skin penetration.
 32. A topical, foamablecomposition comprising: (a) ketoconazole; (b) at least one surfactantselected from the group consisting of ethoxylated sorbitan stearate,ethoxylated sorbitan palmitate, ethoxylated sorbitan oleate, a nonylphenol ethoxylate and a fatty alcohol ethoxylate; (c) a lower alcoholcontent of greater than 10% by weight; (d) water; (e) a long chainalcohol; (f) hydrocarbon gas propellant in an amount of less than 60% byweight; and wherein the composition is a temperature-sensitive,quick-breaking foam or mousse, and wherein the composition has aresidual non-volatile component content of less than 25% by weight andis maintained at a pH ranging from approximately 7 to approximately 8.33. A method for treating fungal diseases, comprising: (a) providing atopical, foamable composition which in use produces a temperaturesensitive, quick-breaking foam or mousse, the composition comprising:ketoconazole, wherein the ketoconazole is capable of penetrating theupper layers of skin of a user, at least one surfactant, water, a loweralcohol, a long chain alcohol, and a hydrocarbon gas propellant contentof less than 60% by weight; and wherein the composition has a residualnon-volatile component content of less than 25% by weight and ismaintained at a pH ranging from approximately 7 to approximately 8; and(b) applying the topical, foamable composition to the user's skin,wherein upon application of the composition to the user's skin, apenetration of at least 30 μg/cm² is achieved in the user's epidermiswithin one hour of application and sustained over a period of at least23 hours.
 34. A method for treating fungal diseases, comprising: (a)providing a topical, foamable composition which in use produces atemperature sensitive, quick-breaking foam or mousse, the compositioncomprising: ketoconazole, wherein the ketoconazole is capable ofpenetrating the upper layers of skin of a user, at least one surfactant,water, a lower alcohol, a long chain alcohol, and a hydrocarbon gaspropellant content of less than 60% by weight; and wherein thecomposition has a residual non-volatile component content of less than25% by weight and is maintained at a pH ranging from approximately 7 toapproximately 8; and (b) applying the topical, foamable composition tothe user's skin, wherein the composition remains on the user's skin foran extended period of time such that the ketoconazole is retained in oron skin for a period of time sufficient to achieve skin penetration.